4-Deoxy-4-substituted amino derivatives of oleandomycin

ABSTRACT

Derivatives of oleandomycin, its 11-monoalkanoyl and 11,2&#39;-dialkanoyl esters having at the 4&#34;-position an amino group substituted with phenyl, benzyl or heterocyclylmethyl groups which may be substituted or unsubstituted, their preparation, and use as antibacterial agents is described.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a structurally unique group of macrolides and,more particularly, to derivatives of oleandomycin, its 11-mono- and11,2'-dialkanoyl esters having at the 4"-position an amino groupsubstituted with phenyl, benzyl or heterocyclylmethyl groups which maybe substituted or unsubstituted, and to a method for their preparation.The compounds are antibacterial agents.

2. Description of the Prior Art

Oleandomycin, a macrolide antibiotic produced by fermentation, was firstdescribed in U.S. Pat. No. 2,757,123. It has the formula, the absoluteconfiguration of which is shown below: ##STR1## It consists of threemain structural features: the L-oleandrose moiety, the desosamine moietyand the oleandolide moiety.

Derivatization of oleandomycin has focused primarily upon the formationof esters at one or more of three hydroxy groups located at the 2',4"and 11-positions. Mono-, di- and triacyl esters wherein the acyl moietyis derived from a lower aliphatic hydrocarbon monocarboxylic acid havingfrom two to six carbon atoms are described in U.S. Pat. No. 3,022,219.

Aminohydrin derivatives of oleandomycin are reported by Kastrons etatl., Khim. Geterosikl Soedin (2), 168-71 (1974); C.A.80, 145986n(1974). The compounds, for which no utility is reported, are prepared bytreating oleandomycin with a dialkylamine or a heterocyclic amine in asealed tube for 20 hours at 30° C. The epoxide moiety at the 8-positionis the site of reaction.

SUMMARY OF THE INVENTION

There has now been found a series of oleandomycin derivatives each ofwhich exhibits valuable antibacterial activity in vitro and many ofwhich exhibit in vivo activity by the parenteral and oral routes ofadministration, particularly against Gram-positive microorganisms. Thecompounds of this invention have formula II below wherein the wavy lineconnecting the substituted amino group at the 4"-position is generic toand embracive of both epimeric forms: ##STR2## wherein each of R₁ and R₂is selected from the group consisting of hydrogen, and alkanoyl havingfrom two to three carbon atoms (acetyl and propionyl); Z is selectedfrom the group consisting of a first subgroup consisting of ##STR3## asecond subgroup consisting of ##STR4## and a third subgroup consistingof

    --CH.sub.2 -heterocyclyl;

wherein

X is selected from the group consisting of hydrogen, chloro, bromo,fluoro, alkyl having from one to four carbon atoms, alkoxy having fromone to four carbon atoms, hydroxy, mercapto, trifluoromethyl, N(CH₃)₂,cyano, thioalkyl having from one to four carbon atoms, sulfonylalkylhaving from one to four carbon atoms, sulfamyl, sulfo, carbamyl,hydroxymethyl and carbalkoxy having from one to four carbon atoms in thealkoxy group;

X₁ is selected from the group consisting of chloro, bromo, fluoro,methyl, methoxy, hydroxy, mercapto and trifluoromethyl;

Y is selected from the group consisting of chloro, bromo, fluoro,methyl, methoxy and hydroxy;

and X₁ and Y when taken together are located on adjacent carbon atomsand are alkylenedioxy and are selected from the group consisting ofmethylenedioxy and ethylenedioxy;

and heterocyclyl is selected from the group consisting of (a) (2- and3-)thienyl, (2- and 3-)furyl, (2-, 3- and 4-)pyridyl and (2- and3-)pyrrolyl and substituted derivatives thereof wherein the substituentis selected from the group consisting of methyl, chloro, bromo, hydroxyand hydroxymethyl, and (b) 2-tetrahydrofuryl, 2-dihydropyranyl,2-tetrahydropyranyl and morpholino.

Also included in the present invention are the pharmaceuticallyacceptable salts of compounds of formula II above. Representative ofsuch salts, but not limited thereto, are the hydrochloride,hydrobromide, phosphate, sulfate, formate, acetate, propionate,butyrate, citrate, glycolate, lactate, tartrate, malate, maleate,fumarate, gluconate, stearate, mandelate, pamoate, benzoate, succinate,lactate, p-toluenesulfonate, and aspartate.

Favored because of their greater biological activity relative to that ofother compounds described herein are compounds of formula II wherein R₁is acetyl, R₂ is hydrogen, and Z has the values shown below:

    ______________________________________                                        Z          X            X.sub.1  Y                                            ______________________________________                                        first subgroup                                                                           H and 2-X    OCH.sub.3                                                                              OCH.sub.3                                    second subgroup                                                                          H and 2-X    OH, Cl   OCH.sub.3, Cl                                third subgroup                                                                           O or N contain-                                                               ing heterocyclyl                                                   ______________________________________                                    

Preferred compounds are those wherein R₁ is acetyl; R₂ is hydrogen and Zhas the values shown below.

    ______________________________________                                        Z            X           X.sub.1   Y                                          ______________________________________                                        first subgroup                                                                             H, 2-OCH.sub.3, 2-F                                                                       2-OCH.sub.3                                                                             4-OCH.sub.3                                                         or                                                                            3-OCH.sub.3                                          second subgroup                                                                            H           4-OH      4-Cl                                                                or                                                                            3-Cl                                                 third subgroup                                                                             pyridyl, furyl, 2-dihydropyranyl,                                             2-tetrahydropyranyl                                              ______________________________________                                    

Compounds of formula II, including the epimeric forms thereof, and theirpharmaceutically acceptable salts are effective antibacterial agentsagainst Gram-positive microorganisms, e.g., Staphylococcus aureus andStreptococcus pyogenes, in vitro and many are active in vivo via theparenteral and oral routes of administration. Many of the compounds (andtheir salts) are also active against certain Gram-negativemicroorganisms, such as cocci, e.g. Pasteurella multocida and Neisseriasicca.

DETAILED DESCRIPTION OF THE INVENTION

The structurally unique oleandomycin derivatives of this invention offormula II are prepared by reaction of the appropriate ketone of formulaIII: ##STR5## wherein each of R₁ and R₂ is as previously defined, withthe appropriate amine (H₂ N-Z) reactant in a reaction-inert solvent toform an intermediate Schiff base compound which is then reduced to thecorresponding substituted amino derivative. Alternatively, rather thanconduct the process in this stepwise fashion, the overall process, areductive amination, can be carried out by reacting a formula IIIcompound and an appropriate amine (H₂ N-Z) in the presence of a suitablereducing agent. The reaction when conducted in this manner is considereda one-step process since all reactants are added simultaneously, or boththe ketone reactant and reducing agent are added simultaneously to theamine reactant, or the amine reactant and reducing agent are addedsimultaneously to the ketone. Regardless of the manner in which thereaction is carried out, the overall reaction is a reductive aminationof the ketone (formula III) as previously noted. Since the aminereactant and reducing agent are more readily available than are theketone compound of formula III, it is preferred to carry out thereaction in a stepwise manner to first form the intermediate Schiff basewhich is then reduced. The Schiff base intermediate need not be isolatedbut can be if desired. An inert atmosphere can be used but is notrequired. Regardless of the manner in which it is carried out, theprocess is generally conducted in a reaction-inert solvent; i.e., onewhich does not react with reactants or products.

The molar ratio of ketone compound to amine reactant can vary widely,e.g., from about 1:1 to about 1:10. Molar ratios of less than 1:1 areavoided for economic reasons to insure maximum reaction of the ketonecompound, normally the least available of the reactants. Ratios ofgreater than 1:10 are seldom used since they do not appear to improvethe yield of final product.

Suitable reaction-inert solvents are alcohols having from one to fourcarbon atoms, ethylene glycol, propylene glycol, tetrahydrofuran,dioxane, diethyl ether, benzene, toluene, acetonitrile, methylenechloride. The favored solvents are polar solvents such as alcohols andacetonitrile which afford a faster rate of reaction relative to that ofnon-polar solvents. When using a 2'-alkanoyl or an 11,2'-dialkanoylderivative of formula III or IV as reactant, a secondary alcohol, andpreferably isopropanol, is used as solvent to avoid removal of the2'-alkanoyl group; unless, of course, removal of such group is desired.

The reaction can be carried out at temperatures from about -10° to about50° C. The temperature range of from about 10° to about 30° C. isfavored since it permits a satisfactory rate of reaction andsatisfactory yields of product.

The reaction between the ketone and amine reactant is acid-catalyzed.For convenience, the amine reactant is generally used in the form of anacid addition salt with a strong mineral acid, e.g., hydrochloric,hydrobromic, hydriodic, sulfuric, nitric or phosphoric acid.Alternatively, the amine reactant can be used as the free base form andthe appropriate acid added to form the acid addition salt in situ. Thehydrochloride salts are the favored acid addition salts primarilybecause of their availability. The presence of the acid addition saltform of the amine reactant tends to accelerate Schiff base formation andto increase the yield of desired product. The molar ratio of acid toamine reactant used is desirably in the range of from about 0.5:1.0 to1:1.5. At ratios outside these ranges, the yield of the final product isreduced. Best results are generally achieved with equimolar orapproximately equiomolar proportions (e.g., 0.8:1 to 1:1.2) of acid toamine reactant.

An alternative method for preparing compounds of this invention whereinZ is selected from the second or third subgroups comprises condensationof the appropriate aldehyde Z₁ -CHO with the appropriate amine reactantof formula IV: ##STR6## in a reaction-inert solvent at a temperature offrom about -10° to about 50° C. The reaction mixture thus produced,which is believed to contain a Schiff base, is then treated with areducing agent to produce the desired product having formula II. Thisprocess is conducted under essentially the same conditions as arerecited above for the first method. The only parameter in which adifference exists, and this only a minor difference, is the temperaturerange. The second method appears to permit a somewhat lower range as thepreferred range; namely, from about -10° to 10° C.

The reaction of this method is also acid catalyzed. The amine reactantof formula IV can be in the form of an acid addition salt with any of avariety of acids, such as a strong mineral acid. e.g., hydrochloric,hydrobromic, hydriodic, sulfuric, nitric or phosphoric acid; an alkanoicacid having from one to four carbon atoms, e.g., formic, acetic,propionic or butyric acids. Alternatively, said amine reactant can beused as the free base form and an appropriate acid added to form theacid addition salt in situ. The acetate and hydrochloride salts are thefavored acid addition salts primarily because of their availability. Thepresence of the acid addition salt form of the amine reactant tends toaccelerate Schiff base formation and to increase the yield of desiredproduct. The molar ratio of acid to amine reactant used is desirably inthe range of from about 0.5:1.0 to 1:1.5. At ratios outside theseranges, the yield of the final product is reduced. Best results aregenerally achieved with equimolar or approximately equimolar proportions(e.g., 0.8:1 to 1:1.2) of acid to amine reactant.

While in principle a variety of reducing agents can be used in eithermethod to achieve the overall reaction of reductive amination, inpractice care must be exercised in the choice of reducing agents becauseof the presence of other reducible groups in the ketone reactant(formula III) or amine reactant (formula IV).

The favored reducing agent is sodium cyanoborohydride since iteffectively accomplishes only the desired reduction and requiresrelatively mild conditions. Further, it is not affected by by-productwater present in the reaction mixture. It is used in molar ratios offrom about one to about three moles per mole of ketone reactant offormula III or of formula Z-CHO.

Other reducing agents which can be used are hydrogen in the presence ofpalladium-on-charcoal and borane-dimethylamine complex.

The above-described processes generate water which need not be removedfrom the reaction mixtures. However, if desired, the by-product watercan be removed by conducting the reaction at reduced pressure or by"effectively" removing it by the use of molecular sieves as adsorbentfor the water. Suitable adsorbents are the natural and syntheticcrystalline aluminosilicates. The latter adsorbents are favored becauseof their greater water-loading capacity relative to the naturalcrystalline aluminosilicates. Included among such adsorbents arechabazite, a naturally occurring material, the synthetic "LindeMolecular Sieves" produced and distributed by the Linde Company, such asTypes 4A, 5A and 13X, and the "Microtraps" produced by the DavisonChemical Company. Such materials sorb and thus effectively remove waterfrom the reaction medium. The exhausted or partially exhaustedaluminosilicate is separated from the reaction mixture by filtration ordecantation.

When using a molecular sieve to effectively remove by-product water, itis necessary to use a reaction-insert solvent such as benzene, toluene,dimethyl sulfoxide, ethanol or propanol. Atmospheric pressure is favoredfor reasons of simplicity of equipment and ease of operation althoughsub- or superatmospheric pressures can be used if desired. The quantityof molecular sieve to be used depends upon the reaction conditions suchas temperature, solvent, and on the nature of the molecular sieve itselfand is best determined by experiment. In general, however, a quantitysufficient to sorb the theoretical amount of by-product water should beused. In actual practice an excess of molecular sieve is advantageoussince it assures more complete reaction.

The reaction mixture, free of molecular sieve, is then reduced asdescribed above.

When the formula III reactant is an 11-monoalkanoyl or 11-hydroxyderivative, the reaction produces a mixture of epimers (represented by awavy line in formula II compounds) which can be separated, if desired.Column chromatography of a chloroform solution of the crude product onsilica gel and elution with appropriate solvents, e.g., chloroform-3%methanol, offers a convenient method for separating the epimers. In thepresent description and illustrations, it is understood that althoughthe compounds are listed as 4"-substituted amino derivatives, bothepimers and mixtures thereof are included.

It has been observed that when an11,2'-dialkanoyl-4"-deoxy-4"-oxooleandomycin is reacted with theherein-described aniline reactants, as described above, the productconsists predominantly of a single epimer.

Diester compounds of formula II; i.e., each of R₁ and R₂ is alkanoyl,can also be prepared by acylation of the corresponding 11-monoalkanoyl(R₁ = alkanoyl; R₂ = H) compound by standard procedures known to thoseskilled in the art, and as exemplified herein. In this manner,preparation of diester compounds wherein the ester groups differ isreadily achieved.

Acid addition salts of the compounds of this invention are readilyprepared by treating formula II compounds with an equimolar amount ofthe appropriate acid in a reaction-inert solvent for the formula IIcompound. The acid addition salts are recovered by filtration if theyare insoluble in the reaction-inert solvent, by precipitation, byaddition of a non-solvent for said salt, or by evaporation of thesolvent.

The 11-mono-alkanoyl- and 11,2'-dialkanoyl-4"-deoxy-4"-oxo-oleandomycinreactants (formula III) are prepared by oxidation of the appropriate11,2'-dialkanoyl-oleandomycin with, for example, N-chlorosuccinimide, tothe corresponding 11,2'-dialkanoyl-4"-deoxy-4"-oxo-oleandomycin.Solvolysis of the diester by treatment with methanol affords the11-monoester product. In like manner, 4"-deoxy-4"-oleandomycin isprepared from 2'-alkanoyl-oleandomycin by oxidation and hydrolysis.

The 11-mono-alkanoyl- and11,2'-dialkanoyl-4"-deoxy-4"-amino-oleandomycin reactants (formula IV)are prepared by reductive amination of the corresponding11-mono-alkanoyl-, 2'-monoalkanoyl- and11,2'-dialkanoyl-4"-deoxy-4"-oxo-oleandomycins usingpalladium-on-charcoal, hydrogen and ammonium acetate in a suitablesolvent, (CH₃ OH, i--C₃ H₇ OH). Alternatively, sodium cyanoborohydridecan be used as reducing agent in place of palladium-on-charcoal andhydrogen. The de-esterified derivative is conveniently prepared byhydrolysis of the corresponding2'-monoalkanoyl-4"-deoxy-4"-amino-oleandomycins.

The novel oleandomycin derivatives described herein exhibit in vitroactivity against a variety of Gram-positive microorganisms and againstcertain Gram-negative microorganisms such as those of spherical orellipsoidal shape (cocci). Their activity is readily demonstrated by invitro tests against various microorganisms in a brain-heart infusionmedium by the usual two-fold serial dilution technique. Their in vitroactivity renders them useful for topical application in the form ofointments, creams and the like; for sterilization purposes, e.g.,sick-room utensils; and as industrial antimicrobials, for example, inwater treatment, slime control, paint and wood preservation.

For in vitro use, e.g., for topical application, it will often beconvenient to compound the selected product with apharmaceutically-acceptable carrier such as vegetable or mineral oil oran emollient cream. Similarly, they may be dissolved or dispersed inliquid carriers or solvents, such as water, alcohol, glycols or mixturesthereof or other pharmaceutically-acceptable inert media; that is, mediawhich have no harmful effect on the active ingredient. For suchpurposes, it will generally be acceptable to employ concentrations ofactive ingredients of from about 0.01 percent to about 10 percent byweight based on total composition.

Additionally, many compounds of this invention are active versusGram-positive and certain Gram-negative microorganisms in vivo via theoral and/or parenteral routes of administration in animals, includingman. Their in vivo activity is more limited as regards susceptibleorganisms and is determined by the usual procedure which comprisesinfecting mice of substantially uniform weight with the test organismand subsequently treating them orally or subcutaneously with the testcompound. In practice, the mice, e.g. 10, are given an intraperitonealinoculation of suitably diluted cultures containing approximately 1 to10 times the LD₁₀₀ (the lowest concentration of organisms required toproduce 100% deaths). Control tests are simultaneously run in which micereceive inoculum of lower dilutions as a check on possible variation invirulence of the test organism. The test compound is administered 0.5hour post-inoculation, and is repeated four, 24 and 48 hours later.Surviving mice are held for four days after the last treatment and thenumber of survivors is noted.

When used in vivo, these novel compounds can be administered orally orparenterally, e.g., by subcutaneous or intramuscular injection, at adosage of from about 1 mg./kg. to about 200 mg./kg. of body weight perday. The favored dosage range is from about 5 mg./kg. to about 100mg./kg. of body weight per day and the preferred range from about 5mg./kg. to about 50 mg./kg. of body weight per day. Vehicles suitablefor parenteral injection may be either aqueous such as water, isotonicsaline, isotonic dextrose, Ringer's solution, or nonaqueous such asfatty oils of vegetable origin (cotton seed, peanut oil, corn, sesame),dimethylsulfoxide and other non-aqueous vehicles which will notinterfere with therapeutic efficiency of the preparation and arenon-toxic in the volume or proportion used (glycerol, propylene glycol,sorbitol). Additionally, compositions suitable for extemporaneouspreparation of solutions prior to administration may advantageously bemade. Such compositions may include liquid diluents; for example,propylene glycol, diethyl carbonate, glycerol, sorbitol, etc.; bufferingagents, hyaluronidase, local anesthetics and inorganic salts to afforddesirable pharmacological properties. These compounds may also becombined with various pharmaceutically-acceptable inert carriersincluding solid diluents, aqueous vehicles, non-toxic organic solventsin the form of capsules, tablets, lozenges, troches, dry mixes,suspensions, solutions, elixirs and parenteral solutions or suspensions.In general, the compounds are used in various dosage forms atconcentration levels ranging from about 0.5 percent to about 90 percentby weight of the total composition.

In the Examples presented herein, no effort was made to recover themaximum amount of product produced or to optimize the yield of a givenproduct. The Examples are merely illustrative of the process and of theproducts obtainable thereby.

EXAMPLE 1 11-Acetyl-4"-deoxy-4"-anilino-oleandomycin

To a solution of aniline (15.0 g., 0.16 mole) in methanolic-hydrogenchloride (65 ml., 0.16 mole, of 2.5 molar) under an atmosphere ofnitrogen and cooled in an ice bath is added with stirring a solution of11-acetyl-4"-deoxy-4"-oxo-oleandomycin (20.0 g., 0.027 mole) in methanol(100 ml.). The resulting amber-colored solution is stirred for fifteenminutes and is then treated dropwise with sodium cyanoborohydride (1.45g., 0.0198 mole) in methanol (70 ml.) over a period of 1.5 hours. Thereaction mixture is stirred for an additional three hours and is thenpoured into a mixture of ethyl acetate (1.2 l.) and water (1.2 l.). ThepH is adjusted to 9.5 (aqueous 6N NaOH) and the aqueous layer discarded.Fresh water (1.2 l.) is added to the ethyl acetate solution and the pHadjusted to 4.0 with hydrochloric acid (6N). The ethyl acetate phase isseparated, water (1.2 l.) added and the pH brought to 9.5 by means ofaqueous sodium hydroxide. The ethyl acetate phase is separated, washedwith water (2 × 500 ml.), saturated with sodium chloride solution (1 ×500 ml.) and then dried (Na₂ SO₄). Evaporation under reduced pressureaffords an amber oil (25 g.).

The oil is dissolved in chloroform (50 ml.) and chromatographed on asilica gel (400 g.) column (60 cm. × 4 cm.) using chloroform-4% methanolas eluant. Ten ml. fractions are collected. Fractions 261-310 arecombined and concentrated under reduced pressure to give 5.85 g. ofimpure product as a white foam. The foam is taken up in acetone (50 ml.)and chromatographed on a silica gel (400 g.) column (60 cm. × 4 cm.)using acetone as eluant. Fractions (10 ml. each) 61-240 are combined andevaporated to dryness under reduced pressure. Yield 4.0 g., m.p.99°-109° C. of a mixture of epimeric anilino substituted products.

Mass Spec. m/e = 158, 220, 351.

NMR (60 MHz) δ_(CDCl).sbsb.3^(TMS) (ppm): 7.00 (bm, 5H), 3.46 (s,1H),3.43 (s, 2H), 2.70 (m, 2H), 2.33 (s, 6H), 2.10 (s, 3H).

The following compounds are similarly prepared but using the appropriatesubstituted aniline in place of aniline. In the table below, the columnheaded C₁ indicates the solvent system used to purify the products viasilica gel chromatography. Only one such treatment was used. In eachinstance a mixture of epimeric substituted anilino products is obtained.

    __________________________________________________________________________     ##STR7##                                                                     Substituted Aniline                                                              Ke-                                                                           tone                    yield                                                                            MS                       M.P..sup.(a)           Ex.                                                                              g. g. X     Y    C.sub.1                                                                              (g.)                                                                             (m/e)                                                                             NMR (60 MHz) δ.sup.TMS.sub.CDCl.sb                                      sb.3 (ppm)           (° C.)                                                                      R.sub.1.sup.(b                                                                )                 __________________________________________________________________________     2 3.0                                                                              4.5                                                                              2-F   H    acetone                                                                              0.66   6.93(bm,4H),3.46(s,1H),3.40(s,2H),2.71(m                                      ,                         Ac                                                  2H),2.46(s,2H),2.43(s,4H),2.10(s,3H).        3 3.0                                                                              4.5                                                                              3-F   H    acetone       6.40(bm,4H),3.43(s,1H),3.40(s,2H),2.66(m                                      ,                         Ac                                                  2H),2.33(s,6H),2.10(s,3H).                   4 3.0                                                                              4.5                                                                              4-F   H    acetone       6.73(q,4H),3.43(s,1H),3.40(s,2H),2.65(m,                                      p                         Ac                                                  2H),2.31(s,6H),2.08(s,3H).                   5 5.0                                                                              8.3                                                                              2-OCH.sub.3                                                                         H    acetone                                                                              0.54                                                                             158,250                                                                           6.80(m,4H),3.90(s,2H),3.86(s,1H),3.43(s,                                      r                    98-100                                                                             Ac                                                  1H),3.40(s,2H),2.66(m,2H),2.36(s,6H),2.1                                      0                                                                             (s,3H).                                      6 5.0                                                                              4.1                                                                              3-OCH.sub.3                                                                         H    CHCl.sub.3                                                                           0.85                                                                             158,250,                                                                          6.28(m,4H),3.78(s,3H),3.43(s,1H),3.38(s,                                      d                    93-104                                                                             Ac                                    4% CH.sub.3 OH                                                                          335,351,                                                                          2H),2.70(m,2H),2.30(s,6H),2.08(s,3H).                                     411.                                             7 5.0                                                                              4.1                                                                              4-OCH.sub.3                                                                         H    CHCl.sub.2                                                                           1.1                                                                              158,250,                                                                          6.76(q,4H),3.76(s,3H),3.43(s,1H),3.40(s,                                      u                    94-100                                                                             Ac                                    3% CH.sub.3 OH                                                                          351,411.                                                                          2H),2.70(m,2H),2.30(s,6H),2.10(s,3H).        8 5.0                                                                              8.6                                                                              2-Cl  H    acetone                                                                              0.92                                                                             158,174,                                                                          6.88(m,4H),3.45(s,1H),3.41(s,2H),2.66(m,                                      c                    90-95                                                                              Ac                                              254,256,                                                                          2H),2.36(s,6H),2.10(s,3H).                                                351.                                             9 5.0                                                                              4.3                                                                              3-Cl  H    CHCl.sub.3                                                                           1.5                                                                              158,254,                                                                          6.90(bm,4H),3.46(s,1H),3.40(s,2H),2.70(m                                      ,                    109-120                                                                            Ac                                    3% CH.sub.3 OH                                                                          256,351.                                                                          2H),2.33(s,2H),2.10(s,3H).                  10 5.0                                                                              4.3                                                                              4-Cl  H    CHCl.sub.3                                                                           1.8                                                                              158,254,                                                                          6.93(q,4H),3.43(s,1H),3.40(s,2H),2.66(m,                                      s                    107-118                                                                            Ac                                    4% CH.sub.3 OH                                                                          256,351.                                                                          2H),2.30(s,6H),2.10(s,3H).                  11 5.0                                                                              5.8                                                                              2-Br  H    CHCl.sub.3                                                                           2.0                                                                              158,298,                                                                          7.03(m,4H),3.43(s,1H),3.40(s,2H),2.66(m,                                      m                    97-109                                                                             Ac                                    4% CH.sub.3 OH                                                                          300,351.                                                                          2H),2.30(s,6H),2.06(s,3H).                  12 5.0                                                                              5.8                                                                              4-Br  H    CHCl.sub.3                                                                           2.0                                                                              158,298,                                                                          6.63(q,4H),3,41(s,1H),3.38(s,2H),2.66(m,                                      a                         Ac                                    4% CH.sub.3 OH                                                                          300,351.                                                                          2H),2.30(s,6H),2.06(s,3H).                  13 5.0                                                                              5.4                                                                              2-CF.sub.3                                                                          H    acetone                                                                              0.59                                                                             158,288,                                                                          6.91(bm,4H),3.83(s,3H),2.65(m,2H),2.33(s                                      ,                    99-108                                                                             Ac                                              351.                                                                              6H),2.08(s,3H).                             14 5.0                                                                              3.6                                                                              2-CH.sub.3                                                                          H    acetone                                                                              1.3                                                                              158,234,                                                                          7.00(m,4H),3.46(s,1H),3.36(s,2H),2.70(m,                                      2H),                 100-112                                                                            Ac                                              351.                                                                              2.33(s,6H),2.20(s,2H),2.16(s,1H),2.10(s,                                      3H).                                        15 5.0                                                                              3.6                                                                              3-CH.sub.3                                                                          H    CHCl.sub.3                                                                           1.0                                                                              158,234,                                                                          2.70(s,2H),2.31(s,6H),2.30(s,3H),2.10(s,                                      3H).                                                            4% CH.sub.3 OH                                                                          335,351,                                                                      411.                                            16 5.0                                                                              3.6                                                                              4-CH.sub.3                                                                          H    acetone                                                                              2.1                                                                              158,234,                                                                          2.33(s,6H),2.26(s,3H),2.10(s,3H).                                                                  99-108                                                                             Ac                                              351.                                            17 5.0                                                                              4.0                                                                              2-CN  H    acetone                                                                              0.35                                                                             158,174,                                                                          2.66(m,2H),2.35(s,3H),2.11(s,3H).                                                                  98-110                                                                             Ac                                              245,351,                                                                      411.                                            18 5.0                                                                              4.1                                                                              2-CH.sub.2 OH                                                                       H    CHCl.sub.3                                                                           0.88                                                                             158,250,                                                                          6.96(m,4H),4.73(bs,2H),3.33(s,3H),2.68(m                                      ,                         Ac                                    4% CH.sub.3 OH                                                                          335,351,                                                                          2H),2.31(s,6H),2.10(s,3H).                                                411.                                            19 10.0                                                                             10.2                                                                             2-COOCH.sub.3                                                                       H    CHCl.sub.3                                                                           1.7                                                                              158,278,                                                                          7.03(bm,4H),3.88(s,3H),3.45(s,1H),3.36(s                                      ,                         Ac                                    3% CH.sub.3 OH                                                                          335,351,                                                                          2H),2.70(m,2H),2.31(s,6H),2.08(s,3H).                                     411.                                            20.sup.(c)                                                                       2.3                                                                              3.0                                                                              2-N(CH.sub.3).sub.2                                                                 H    CHCl.sub.3                                                                           0.74                                                                             158,263                                                                           6.71(s,4H),3.38(s,3H),3.81(s,6H),2.66(m,                                      2H),                      Ac                                    3% CH.sub.3 OH                                                                          335,351,                                                                          2.33(s,6H),2.08(s,3H).                                                    411.                                            21 5.0                                                                              4.6                                                                              2-CONH.sub.2                                                                        H    CHCl.sub.3                                                                              158,263,                                                                          4.05(m,4H),3.45(s,1.5H),3.36(s,1.5H),2.6                                      8                    125-135                                                                            Ac                                    3% CH.sub.3 OH                                                                          350.                                                                              (m,2H),2.31(s,6H),2.06(s,3H).               22 3.0                                                                              4.4                                                                              4-OH  H    CHCl.sub.3                                                                           0.72   6.71(m,4H),3.45(s,1H),3.40(s,2H),2.70(m,                                      2H),                 114(dec.)                                                                          Ac                                    2% CH.sub.3 OH                                                                              2.33(s,6H),2.10(s,3H).                      23 5.0                                                                              4.1                                                                              2-CH.sub.3                                                                          6-CH.sub.3                                                                         CHCl.sub.3                                                                           0.60                                                                             158,248,                                                                          6.51(m,3H),3.18(s,3H),2.68(m,2H),2.33(s,                                      9H),                      Ac                                    3% CH.sub.3 OH                                                                          335,351.                                                                          2.20(s,3H),2.08(s,3H).                      24 5.0                                                                              4.7                                                                              2-CH.sub.3                                                                          4-Cl CHCl.sub.3                                                                           1.7                                                                              158.268,                                                                          6.90(m,3H),3.43(s,1H),3.38(s,2H),2.70(m,                                      2H),                      Ac                                    4% CH.sub.3 OH                                                                          270,335,                                                                          2.33(s,6H),2.21(s,3H),2.10(s,3H).                                         351,411.                                        25 5.0                                                                              5.5                                                                              3-Cl  4-Cl CHCl.sub.3                                                                           2.2                                                                              158,288,                                                                          7.20(s,1H),6.76(m,2H),3.46(2,1H),3.40(s,                                      2H),                 98-114                                                                             Ac                                    4% CH.sub.3 OH                                                                          290,292                                                                           2.70(m,2H),2.30(s,6H),2.10(s,3H).                                         335,351,                                                                      411.                                            26 5.0                                                                              5.2                                                                              2-OCH.sub.3                                                                         4-OCH.sub.3                                                                        CHCl.sub.3                                                                           1.4                                                                              158,280,                                                                          6.46(m,3H);3.83(s,2H),3.76(s,4H),3.40(s,                                      1H),                 99-107                                                                             Ac                                    4% CH.sub.3 OH                                                                          335.                                                                              3.36(s,2H),2.66(s,2H),2.30(s,6H),2.06(s,                                      3H).                                        27 2.5                                                                              2.5                                                                              3-OCH.sub.3                                                                         4-OCH.sub. 3                                                                       CHCl.sub.3                                                                           0.28                                                                             158,280                                                                           6.58(m,3H),3.88(s,3H),3.81(s,3H),3.41(s,                                      3H),                 98-108                                                                             Ac                                    4% CH.sub.3 OH                                                                          335,351,                                                                          2.70(m,2H),2.31(s,6H),2.08(s,3H).                                         411.                                            28 5.0                                                                              5.2                                                                              3-OCH.sub.3                                                                         5-OCH.sub.3                                                                        CHCl.sub.3                                                                           1.1                                                                              158.280,                                                                          5.96(m,3H),3.81(s,6H),3.46(s,1H),3.43(s,                                      2H),                      Ac                                    4% CH.sub.3 OH                                                                          335,351                                                                           2.71(s,2H),2.35(s,6H),2.11(s,3H).                                         411.                                            29 3.5                                                                              9.7                                                                              3-CF.sub.3                                                                          2-Cl CHCl.sub.3                                                                           1.5    6.7-7.6(m,aromatic H),3.43(s,3H),2.66(d,                                      2H),                      Ac                                    4% CH.sub.3 OH                                                                              2.33(s,6H),2.10(s,3H).                      30 5.0                                                                              2.0                                                                              2-OCH.sub.3                                                                         H    CHCl.sub.32%                                                                         0.18                                                                             158,250                                                                           6.75(bs,4H),3.86(s,2H),3.78(s,1H),3.40(s                                      ,                         H                                     i-C.sub.3 H.sub.7 OH                                                                        1H),3.36(s,2H),2.83(m,2H),2.16(s,6H).       31 4.0                                                                              5.4                                                                              2-COOCH.sub.3                                                                       H    CHCl.sub.33%                                                                         0.19                                                                             158,278,                                                                          7.4(bm,4H),3.88(s,2H),3.85(s,1H),3.43(s,                                                                H                                     i-C.sub.3 H.sub.7 OH                                                                    386 2H),3.36(s,1H),2.76(m,2H),2.23(s,6H).       __________________________________________________________________________     .sup.(a) The melting points observed are broad since the products are a       mixture of epimers.                                                           .sup.(b) Ac = Acetyl                                                          .sup.(c) The product of Example 20 is extracted with ethyl acetate at pH      6.0.                                                                     

EXAMPLE 32 Epimeric11-Acetyl-4"-deoxy-4"-(2-hydroxyanilino)-oleandomycins

The procedure of Example 1 is repeated but using 5 g. of11-acetyl-4"-deoxy-4"-oxo-oleandomycin, 3.6 g. of o-aminophenol and 310mg. of 85% sodium cyanoborohydride. The reaction mixture is worked upaccording to the procedure of Example 1, the oily reaction product takenup in chloroform and chromatographed on silica gel using chloroform-3%methanol as eluant. Ten ml. fractions are collected. Fractions 81-97contain a mixture of epimers. Fractions 98-150 are found on thin layerchromatography to contain a single compound. Evaporation of the eluateaffords the compounds as a tan solid; m.p. 118°-120° C., 720 mg.

Fractions 151-200 contains a mixture of epimers and fractions 201-250are found to contain a single compound, the epimer of theabove-mentioned product.

The configuration of these two epimeric compounds has not yet beenestablished.

The NMR spectra of these epimers are presented below.

NMR (60 MHz) δ_(CDCl).sbsb.3^(TMS) (ppm):

(a) First Epimer

6.86 (bs, 4H), 3.53 (s, 3H), 2.70 (m,2H), 2.31 (s, 6H), 2.11 (s, 3H).

(b) Second Epimer

6.83 (bm, 4H), 3.51 (s,3H), 2.73 (m,2H), 2.38 (s, 6H), 2.10 (s, 3H).

The mass spectra of the epimers is identical; m/e = 158, 236, 335, 351,411.

EXAMPLE 33

The procedure of Example 1 is repeated but using the appropriate4"-deoxy-4"-oxo-oleandomycin reactant and the appropriate aniline asreactants to produce the following compounds:

    ______________________________________                                         ##STR8##                                                                     R.sub.1       X            Y         R.sub.2                                  ______________________________________                                        COCH.sub.3                                                                              2-C.sub.2 H.sub.5                                                                          H         H                                            COCH.sub.3                                                                              4-C.sub.2 H.sub.5                                                                          H         H                                            COCH.sub.3                                                                              3-n-C.sub.3 H.sub.7                                                                        H         COCH.sub.3                                   COCH.sub.3                                                                              2-i-C.sub.3 H.sub.7                                                                        H         H                                            COCH.sub.3                                                                              2-n-C.sub.4 H.sub.9                                                                        H         COCH.sub.3                                   COCH.sub.3                                                                              4-n-C.sub.4 H.sub.9                                                                        H         H                                            COCH.sub.3                                                                              4-t-C.sub.4 H.sub.9                                                                        H         H                                            COCH.sub.3                                                                              3-CF.sub.3   H         H                                            COCH.sub.3                                                                              4-CF.sub.3   H         COCH.sub.3                                   COCH.sub.3                                                                              3-CONH.sub.2 H         H                                            COCH.sub.3                                                                              2-SH         H         H                                            COCH.sub.3                                                                              4-SH         H         COCH.sub.2 CH.sub.3                          COCH.sub.3                                                                              3-OH         H         H                                            COCH.sub.3                                                                              2-SO.sub.2 NH.sub.2                                                                        H         H                                            COCH.sub.3                                                                              3-SO.sub.2 NH.sub.2                                                                        H         COCH.sub.3                                   COCH.sub.3                                                                              4-SO.sub.3 H H         COCH.sub.3                                   COCH.sub.3                                                                              2-SO.sub.3 H H         H                                            COCH.sub.3                                                                              3-CH.sub.2 OH                                                                              H         H                                            COCH.sub.3                                                                              3-SO.sub.2 CH.sub.3                                                                        H         H                                            COCH.sub.3                                                                              2-OC.sub.2 H.sub.5                                                                         H         COCH.sub.2 CH.sub.3                          COCH.sub.3                                                                              4-O-n-C.sub.4 H.sub.9                                                                      H         H                                            COCH.sub.3                                                                              4-O-i-C.sub.3 H.sub.7                                                                      H         H                                            COCH.sub.3                                                                              4-COOCH.sub.3                                                                              H         COCH.sub.2 CH.sub.3                          COCH.sub.3                                                                              3-COO-n-C.sub.4 H.sub.9                                                                    H         H                                            COCH.sub.3                                                                              4-COOC.sub.2 H.sub.5                                                                       H         H                                            COCH.sub.3                                                                              2-SCH.sub.3  H         H                                            COCH.sub.3                                                                              3-SC.sub.2 H.sub.5                                                                         H         H                                            COCH.sub.3                                                                              4-S-n-C.sub.4 H.sub.9                                                                      H         COCH.sub.3                                   COCH.sub.3                                                                              2-SO.sub.2 CH.sub.3                                                                        H         H                                            COCH.sub.3                                                                              2-SO.sub.2 CH.sub.3                                                                        H         H                                            COCH.sub.3                                                                              4-SO.sub.2 CH.sub.3                                                                        H         H                                            COCH.sub.3                                                                              3-SO.sub.2 C.sub.2 H.sub.5                                                                 H         COCH.sub.3                                   COCH.sub.3                                                                              3-SO.sub.2 C.sub.2 H.sub.5                                                                 H         H                                            COCH.sub.3                                                                              4-SO.sub.2 -n-C.sub.4 H.sub.9                                                              H         COCH.sub.3                                   COCH.sub.3                                                                              4-SO.sub.2 -n-C.sub.4 H.sub.9                                                              H         H                                            COCH.sub.3 2,3-OCH.sub.2O    COCH.sub.3                                       COCH.sub.3 3,4-OCH.sub.2O    H                                                COCH.sub.3 3,4-OCH.sub.2 CH.sub.2O                                                                         H                                                COCH.sub.3 2,3-OCH.sub.2 CH.sub.2O                                                                         COCH.sub.2 CH.sub.3                              COCH.sub.2 CH.sub.3                                                                     2F           H         COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     2-OCH.sub.3  H         H                                            COCH.sub.2 CH.sub.3                                                                     4-OCH.sub.3  H         COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     3-CH.sub.2 OH                                                                              H         H                                            COCH.sub.2 CH.sub.3                                                                     3-CH.sub.3   H         H                                            COCH.sub.2 CH.sub.3                                                                     4-C.sub.2 H.sub.5                                                                          H         H                                            COCH.sub.2 CH.sub.3                                                                     4-t-C.sub.4 H.sub.9                                                                        H         COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     3-CF.sub.3   H         H                                            COCH.sub.2 CH.sub.3                                                                     3-CN         H         H                                            COCH.sub.2 CH.sub.3                                                                     4-CN         H         COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     4-N(CH.sub.3).sub.2                                                                        H         H                                            COCH.sub.2 CH.sub.3                                                                     2-COOCH.sub.3                                                                              H         H                                            COCH.sub.2 CH.sub.3                                                                     4-COO-n-C.sub.4 H.sub.9                                                                    H         COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     3-COOC.sub.2 H.sub.5                                                                       H         H                                            COCH.sub.2 CH.sub.3                                                                     3-Cl         H         H                                            COCH.sub.2 CH.sub.3                                                                     4-Br         H         COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     4-SO.sub.3 H H         H                                            COCH.sub.2 CH.sub.3                                                                     4-Cl         H         COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     H            H         H                                            COCH.sub.2 CH.sub.3                                                                     4-t-C.sub.4 H.sub.9                                                                        H         H                                            COCH.sub.2 CH.sub.3                                                                     3-i-C.sub.3 H.sub.7                                                                        H         H                                            COCH.sub.2 CH.sub.3                                                                     2-C.sub.2 H.sub.5                                                                          H         COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     3-OC.sub.2 H.sub.5                                                                         H         H                                            COCH.sub.2 CH.sub.3                                                                     4-O-n-C.sub.4 H.sub.9                                                                      H         H                                            COCH.sub.2 CH.sub.3                                                                     2-OH         H         COCH.sub.3                                   COCH.sub.2 CH.sub.3                                                                     3-OH         H         H                                            COCH.sub.2 CH.sub.3                                                                     4-OH         H         H                                            COCH.sub.2 CH.sub.3                                                                     2-CONH.sub.2 H         H                                            COCH.sub.2 CH.sub.3                                                                     4-CONH.sub.2 H         H                                            COCH.sub.2 CH.sub.3                                                                     2-SH         H         COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     4-SH         H         H                                            COCH.sub.2 CH.sub.3                                                                     2-SCH.sub.3  H         H                                            COCH.sub.2 CH.sub.3                                                                     3-SCH.sub.3  H         H                                            COCH.sub.2 CH.sub.3                                                                     4-S-n-C.sub.4 H.sub.9                                                                      H         H                                            COCH.sub.2 CH.sub.3                                                                     3-SC.sub.2 H.sub.5                                                                         H         COCH.sub.3                                   COCH.sub.2 CH.sub.3                                                                     2-SO.sub.2 CH.sub.3                                                                        H         H                                            COCH.sub.2 CH.sub.3                                                                     3-SO.sub.2 C.sub.2 H.sub.5                                                                 H         H                                            COCH.sub.2 CH.sub.3                                                                     4-SO.sub.2 -n-C.sub.4 H.sub.9                                                              H         COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     2-SO.sub.2 CH.sub.3                                                                        H         H                                            COCH.sub.2 CH.sub.3                                                                     3-SO.sub.2 C.sub.2 H.sub.5                                                                 H         H                                            COCH.sub.2 CH.sub.3                                                                     4-SO.sub.2 -n-C.sub.4 H.sub.9                                                              H         COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     3-SO.sub.2 NH.sub.2                                                                        H         COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     4-SO.sub.2 NH.sub.2                                                                        H         H                                            COCH.sub.2 CH.sub.3                                                                     2-CH.sub.2 OH                                                                              H         H                                            COCH.sub.2 CH.sub.3                                                                     3-CH.sub.2 OH                                                                              H         COCH.sub.3                                   COCH.sub.2 CH.sub.3                                                                     2-COOCH.sub.3                                                                              H         H                                            COCH.sub.2 CH.sub.3                                                                     4-COO-i-C.sub.3 H.sub.7                                                                    H         H                                            COCH.sub.2 CH.sub.3                                                                     3-COO-n-C.sub.4 H.sub.9                                                                    H         H                                            COCH.sub.2 CH.sub.3                                                                      2,3-OCH.sub.2O    H                                                COCH.sub.2 CH.sub.3                                                                      3,4-OCH.sub.2 CH.sub.2O                                                                         COCH.sub.2 CH.sub.3                              COCH.sub.2 CH.sub.3                                                                      2,3-OCH.sub.2 CH.sub.2O                                                                         H                                                COCH.sub.3                                                                              2-Cl         6-Cl      H                                            COCH.sub.3                                                                              3-Cl         4-Br      H                                            COCH.sub.3                                                                              2-Br         4-F       COCH.sub.3                                   COCH.sub.3                                                                              2-Cl         3-F       H                                            COCH.sub.3                                                                              2-F          4-F       H                                            COCH.sub.3                                                                              2-F          6-F       H                                            COCH.sub.3                                                                              2-CH.sub.3   4-F       COCH.sub.3                                   COCH.sub.3                                                                              3-CH.sub.3   5-Cl      H                                            COCH.sub.3                                                                              4-CH.sub.3   3-Br      H                                            COCH.sub.3                                                                              2-Br         4-OCH.sub.3                                                                             COCH.sub.3                                   COCH.sub.3                                                                              3-Cl         4-OCH.sub.3                                                                             H                                            COCH.sub.3                                                                              4-F          3-OCH.sub.3                                                                             H                                            COCH.sub.3                                                                              2-OH         6-Br      H                                            COCH.sub.3                                                                              2-OH         5-Cl      COCH.sub.2 CH.sub.3                          COCH.sub.3                                                                              5-OH         2-Cl      H                                            COCH.sub.3                                                                              4-OH         3-Cl      H                                            COCH.sub.3                                                                              4-OH         2-F       COCH.sub.2 CH.sub.3                          COCH.sub.3                                                                              2-SH         5-Cl      H                                            COCH.sub.3                                                                              4-SH         3-Cl      COCH.sub.3                                   COCH.sub.3                                                                              4-SH         3-Br      H                                            COCH.sub.3                                                                              4-SH         2-F       H                                            COCH.sub. 3                                                                             2-CF.sub.3   4-F       COCH.sub.3                                   COCH.sub.3                                                                              2-CF.sub.3   4-Br      H                                            COCH.sub.3                                                                              5-CF.sub.3   2-Cl      H                                            COCH.sub.3                                                                              5-CF.sub.3   2-Cl      H                                            COCH.sub.3                                                                              2-CH.sub.3   4-CH.sub.3                                                                              H                                            COCH.sub.3                                                                              2-CH.sub.3   4-OCH.sub.3                                                                             COCH.sub.3                                   COCH.sub.3                                                                              5-CH.sub.3   2-OCH.sub.3                                                                             H                                            COCH.sub.3                                                                              6-CH.sub.3   2-OH      COCH.sub.3                                   COCH.sub.3                                                                              2-CH.sub.3   4-OH      H                                            COCH.sub.3                                                                              5-OCH.sub.3  2-OH      H                                            COCH.sub.3                                                                              4-OCH.sub.3  3-OH      COCH.sub.2 CH.sub.3                          COCH.sub.3                                                                              2-OH         4-OH      H                                            COCH.sub.3                                                                              3-SH         4-OH      H                                            COCH.sub.2 CH.sub.3                                                                     2-OCH.sub.3  4-OCH.sub.3                                                                             H                                            COCH.sub.2 CH.sub.3                                                                     3-OCH.sub.3  5-OCH.sub.3                                                                             COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     3-Cl         4-Cl      H                                            COCH.sub.2 CH.sub.3                                                                     2-CH.sub.3   6-CH.sub.3                                                                              COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     2-F          4-F       COCH.sub.3                                   COCH.sub.2 CH.sub.3                                                                     2-Br         5-F       H                                            COCH.sub.2 CH.sub.3                                                                     3-Br         4-Br      H                                            COCH.sub.2 CH.sub.3                                                                     3-F          2-Cl      COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     4-OCH.sub.3  2-Cl      COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     4-OCH.sub.3  3-Br      H                                            COCH.sub.2 CH.sub.3                                                                     3-OCH.sub.3  4-F       H                                            COCH.sub.2 CH.sub.3                                                                     2-CH.sub.3   4-F       H                                            COCH.sub.2 CH.sub.3                                                                     2-CH.sub.3   4-Cl      H                                            COCH.sub. 2 CH.sub.3                                                                    2-CH.sub.3   5-Br      COCH.sub.2 CH.sub.3                          COCH.sub.3                                                                              4-SH         2-CH.sub.3                                                                              H                                            COCH.sub.3                                                                              5-SH         2-CH.sub.3                                                                              H                                            COCH.sub.3                                                                              2-SH         5-OCH.sub.3                                                                             COCH.sub.2 CH.sub.3                          COCH.sub.3                                                                              5-CF.sub.3   2-CH.sub.3                                                                              H                                            COCH.sub.3                                                                              6-CF.sub.3   3-OCH.sub.3                                                                             COCH.sub.2 CH.sub.3                          COCH.sub.3                                                                              2-CF.sub.3   5-OH      H                                            COCH.sub.2 CH.sub.3                                                                     2-OH         6-OH      COCH.sub.3                                   COCH.sub.2 CH.sub.3                                                                     2-CH.sub.3   4-OCH.sub.3                                                                             H                                            COCH.sub.2 CH.sub.3                                                                     3-CH.sub.3   6-Cl      H                                            COCH.sub.2 CH.sub.3                                                                     2-CH.sub.3   5-OH      H                                            COCH.sub.2 CH.sub.3                                                                     5-CH.sub.3   2-OH      H                                            COCH.sub.2 CH.sub.3                                                                     2-CH.sub.3   6-OH      COCH.sub.3                                   COCH.sub.2 CH.sub.3                                                                     5-OCH.sub.3  2-OH      COCH.sub.3                                   COCH.sub.2 CH.sub.3                                                                     4-OH         2-CH.sub.3                                                                              H                                            COCH.sub.2 CH.sub.3                                                                     5-SH         2-CH.sub.3                                                                              H                                            COCH.sub.2 CH.sub.3                                                                     5-SH         3-OCH.sub.3                                                                             H                                            COCH.sub.2 CH.sub.3                                                                     3-SH         4-OH      COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     3-CF.sub.3   2-CH.sub.3                                                                              H                                            COCH.sub.2 CH.sub.3                                                                     6-CF.sub.3   2-OCH.sub.3                                                                             H                                            COCH.sub.2 CH.sub.3                                                                     2-CF.sub.3   5-OH      H                                            COCH.sub.2 CH.sub.3                                                                     2-CF.sub.3   4-F       COCH.sub.2 CH.sub.3                          COCH.sub.2 CH.sub.3                                                                     3-CF.sub.3   4-Cl      H                                            COCH.sub.2 CH.sub.3                                                                     2-CF.sub.3   4-Br      H                                            COCH.sub. 2 CH.sub.3                                                                    2-CF.sub.3   4-OH      H                                            H         2-Cl         H         H                                            H         2-F          H         H                                            H         4-Br         H         COCH.sub.3                                   H         3-Cl         H         H                                            H         3-F          H         COCH.sub.2 CH.sub.3                          H         2-CH.sub.3   H         H                                            H         2-n-C.sub.4 H.sub.9                                                                        H         COCH.sub.3                                   H         4-t-C.sub.4 H.sub.9                                                                        H         H                                            H         3-C.sub.2 H.sub.5                                                                          H         H                                            H         4-OCH.sub.3  H         H                                            H         3-OC.sub.2 H.sub.5                                                                         H         H                                            H         3-O-i-C.sub.3 H.sub.7                                                                      H         H                                            H         4-O-n-C.sub.4 H.sub.9                                                                      H         COCH.sub.2 CH.sub.3                          H         2-OH         H         H                                            H         4-OH         H         COCH.sub.2 CH.sub.3                          H         3-CN         H         H                                            H         2-CF.sub.3   H         H                                            H         3-CF.sub.3   H         COCH.sub.3                                   H         4-CONH.sub.2 H         H                                            H         2-SH         H         H                                            H         3-SH         H         COCH.sub.3                                   H         2-SCH.sub.3  H         H                                            H         4-S-n-C.sub.4 H.sub.9                                                                      H         H                                            H         2-SO.sub.2 CH.sub.3                                                                        H         COCH.sub.3                                   H         4-SO.sub.2 -n-C.sub.4 H.sub.9                                                              H         COCH.sub.2 CH.sub.3                          H         4-SO.sub.2 -i-                                                                             H         H                                                      C.sub.3 H.sub.7                                                     H         4-SO.sub.2 -t-                                                                             H         COCH.sub.2 CH.sub.3                                    C.sub.4 H.sub.9                                                     H         3-SO.sub.2 NH.sub.2                                                                        H         H                                            H         2-SO.sub.3 H H         H                                            H         3-SO.sub.3 H H         COCH.sub.3                                   H         4-CH.sub.2 OH                                                                              H         H                                            H         3-COOC.sub.2 H.sub.5                                                                       H         H                                            H         4-COO-n-     H         H                                                      C.sub.4 H.sub.9                                                     H          2,3-OCH.sub.2O    H                                                H          3,4-OCH.sub.2 CH.sub.2O                                                                         COCH.sub.3                                       H         2-Cl         6-Cl      COCH.sub.3                                   H         3-Cl         4-Cl      COCH.sub.2 CH.sub.3                          H         2-F          4-F       H                                            H         3-Br         5-Br      H                                            H         2-Cl         4-F       H                                            H         4-Cl         2-Br      COCH.sub.3                                   H         3-Br         4-F       H                                            H         4-F          3-CH.sub.3                                                                              COCH.sub.2 CH.sub.3                          H         2-CH.sub.3   6-Cl      H                                            H         2-CH.sub.3   6-CH.sub.3                                                                              H                                            H         2-CH.sub.3   3-Br      H                                            H         2-CH.sub.3   3-OCH.sub.3                                                                             H                                            H         3-CH.sub.3   4-OH      COCH.sub.3                                   H         2-OCH.sub.3  4-OCH.sub.3                                                                             H                                            H         5-OCH.sub.3  2-OH      COCH.sub.2 CH.sub.3                          H         2-OH         4-OH      H                                            H         4-SH         2-F       H                                            H         2-SH         3-Cl      COCH.sub.3                                   H         2-SH         5-Br      H                                            H         2-CF.sub.3   4-F       COCH.sub.3                                   H         5-CF.sub.3   2-Cl      H                                            H         4-OH         3-Br      H                                            H         4-OH         2-Cl      COCH.sub.2 CH.sub.3                          H         2-CF.sub.3   4-Br      H                                            H         2-SH         4-OH      H                                            H         5-SH         2-CH.sub.3                                                                              H                                            H         3-OCH.sub.3  4-F       COCH.sub.3                                   H         2-SH         5-OCH.sub.3                                                                             H                                            ______________________________________                                    

EXAMPLE 34 11,2'-Diacetyl-4"-deoxy-4"-anilino-oleandomycin

To a solution of aniline hydrochloride (4.1 g., 32 mmoles) inisopropanol (55 ml.) at 0° C. under a nitrogen atmosphere is added11,2'-diacetyl-4"-deoxy-4"-oxo-oleandomycin (5.0 g., 6.5 mmoles). Thereaction mixture is stirred for a half-hour at 0° C. and then sodiumcyanoborohydride (296 mg., 4.7 mmoles) in isopropanol (15 ml.) is addedover a period of 1.5 hours. The reaction mixture is stirred at 0° C. fortwo hours following completion of addition and is then poured into water(200 ml.) layered with ethyl acetate (200 ml.). The pH is adjusted to9.5 with aqueous sodium hydroxide, and the aqueous phase discarded. Theethyl acetate solution which contains the desired product is then workedup according to the procedure of Example 1. The product is contained infractions 130-180 and is isolated by concentration of the eluate underreduced pressure as a white foam (1.5 g.).

Its NMR spectrum showed only a single peak at δ_(CDCl).sbsb.3^(TMS)(ppm) of 3.18.

The 2'-acetyl group is solvolyzed as follows. A solution of11,2'-diacetyl-4"-deoxy-4"-anilino-oleandomycin (400 mg.) in methanol(20 ml.) under a nitrogen atmosphere is stirred at room temperature for18 hours. It is then evaporated to dryness under reduced pressure andthe residue taken up in ether. Upon standing, the 11-monoacetylderivative precipitates. It is filtered, washed with ether and dried invacuo; m.p. 206°-208° C.

NMR δ_(CDCl).sbsb.3^(TMS) (ppm): 6.90 (m, 5H), 3.38 (s, 3H), 2.66 (m,2H), 2.30 (s, 6H), 2.06 (s, 3H).

EXAMPLE 35 11,2'-Diacetyl-4"-deoxy-4"-anilino-oleandomycin (byacetylation of 11-monoacetyl derivative)

Acetic anhydride (0.071 ml., 7.6 mmoles) is added to a solution of11-monoacetyl-4"-deoxy-4"-anilino-oleandomycin (615 mg., 0.76mmoles) inbenzene (15 ml.) under a nitrogen atmosphere at room temperature. Themixture is stirred for three hours and is then poured into water (25ml.) layered with benzene (25 ml.). The pH is adjusted to 9.5 with 6NNaOH and the benzene layer separated. It is washed successively withwater and brine and then dried (Na₂ SO₄) and concentrated under reducedpressure to a foam (600 mg.).

Its NMR spectrum showed peaks at δ_(CDCl).sbsb.3^(TMS) (ppm) of 3.22 and3.18, indicative of a mixture of epimers.

EXAMPLE 36 General Procedure -- Condensation of11-Acetyl-4"-Deoxy-4"-Amino-oleandomycin with an Aromatic Aldehyde11-Acetyl-4"-deoxy-4"-furfurylamino-oleandomycin

To a solution of 11-acetyl-4"-deoxy-4"-amino-oleandomycin (5.0 g., 6.8mmol.) in methanol (15 ml.) at -10° C. and under a nitrogen atmosphereis rapidly added with stirring a solution of furfural (1.65 g., 17.2mmol), acetic acid (0.41 g., 6.8 mmol.) and methanol (20 ml.). Then, asolution of sodium cyanoborohydride (0.37 g. (85%), 5.0 mmol.) inmethanol (20 ml.) is added over a 40 minute period while maintaining thetemperature at about -10° to -5° C. Upon completion of addition, thereaction mixture is stirred at about -5° C. for 75 minutes and is thenpoured into water (150 ml.) layered with ether (150 ml.). The aqueousphase is adjusted to pH 3, separated, and is then extracted with 1Naqueous sodium hydroxide at pH 9-10. The ether extract is dried (Na₂SO₄) and evaporated to give 2.4 g. of the title product as a white foam.It is purified by chromatography on silica gel (200 g.) usingchloroform-methanol (95:5) as eluant. The desired product is the firstmaterial to be eluted. The first 200 ml. of eluant were combined andevaporated to give the title product (470 mg., 8.5%) as an amorphouswhite foam. The product is a mixture of C.4" epimers.

¹ H NMR (60 MH₂) δ_(CDCl).sbsb.3^(TMS) (ppm): 7.3 (m, 1H), 6.16 (m, 2H),3.87 (s, 2H), 3.12 (s, 3H), 2.67 (bs, 2H), 2.28 (s, 6H), 2.03 (s, 3H).

EXAMPLE 37 General Procedure -- Condensation of11-Acetyl-4"-Deoxy-4"-Oxo-oleandomycin with an Aralkylamine11-Acetyl-4"-deoxy-4"-(6-methyl-2-pyridylmethylamino)-oleandomycin

A solution of 2-aminomethyl-6-methylpyridine (8.36 g., 68 mmol.) inacetic acid (4.1 g., 68 mmol.) and methanol (20 ml.) is rapidly addedwith stirring to a solution of 11-acetyl-4"-deoxy-4"-oxo-oleandomycin(5.0 g., 68 mmol.) in methanol (15 ml.) under a nitrogen atmosphere atroom temperature. Then, a solution of sodium cyanoborohydride (0.37 g.[85%], 5.0 mmol.) in methanol (15 ml.) is added and the reaction mixturestirred for one-half hour. It is then poured into water (150 ml.)layered with ether (150 ml.). The aqueous phase is adjusted to pH 3,separated, adjusted to pH 10 with 1N sodium hydroxide solution andextracted with ether. The pH is then raised to 11.6 and the aqueousphase again extracted with ether. The combined extracts are dried (Na₂SO₄) and evaporated to give11-acetyl-4"-deoxy-4"-(6-methyl-2-pyridylmethylamino)-oleandomycin (634mg., 11%) as a light yellow foam. It is a mixture of the C.4" epimers.

Its NMR spectra is:

¹ H NMR (60 MHz) δ_(CDCl).sbsb.3^(TMS) (ppm): 6.80-7.60 (m, 3H), 4.00(s, 2H), 3.35 (s, 3H), 2.63 (bs, H), 2.35 (s, 3H), 2.28 (s, 6H), 2.05(s, 3H).

The following compounds are prepared by the procedures of Examples 36 or37 from the appropriate reactants. A mixture of C.4" epimers is producedin each instance by the process of Example 36. The process of Example 37affords predominantly a single epimer, the stereochemistry of which isnot yet established.

    __________________________________________________________________________     ##STR9##                                                                 

    __________________________________________________________________________         R.sub.1 = acetyl                                                                         Proce-                                                        Example                                                                              Z.sub.1  dure .sup.1 H NMR (60 MHz)δ.sup.TMS.sub.CDCl.sbsb.3                          (ppm)                                                    __________________________________________________________________________    38   C.sub.6 H.sub.5.                                                                         36   7.27-7.33(m,5H), 3.90(s,2H), 3,23(s,3H),                                      2.63(bs,2H), 2.28                                                             (s,6H), 2.03 (s,3H).                                     39                                                                            4-ClC.sub.6 H.sub.4                                                                37         7.3(s,4H), 3.88(s,2H), 3.26(s,3H), 2.63(d,2H), 2.3                            (s,6H),                                                                            2.03(s,3H).                                              40                                                                            3-ClC.sub.6 H.sub.4                                                                37         7.20-7.40(m,4H), 3.93(s,2H), 3.31(s,2H), 3.31(s,3H),                          2.66(d,2H), 2.33                                                                   (s,6H), 2.10(s,3H).                                      41                                                                            4-HOC.sub.6 H.sub.4                                                                36         6.6-7.6(m,4H), 3.33(s,3H), 2.66(d,2H), 2.33(s,6H), 2.06                            (s,3H).                                                  42                                                                            4-CH.sub.3 OC.sub.6 H.sub.4                                                        37         6.7-7.3(m,4H), 3.80(s,5H), 3.35(s,3H), 2.65(bs,2H), 2.28                           (s,6H), 2.05(s,3H).                                      43                                                                            4-CH.sub.3 C.sub.6 H.sub.4 *                                                       37         7.0-7.3(m,4H), 3.85(s,2H), 3.35(s,3H), 2.65(bs,2H), 2.33                           (s,3H), 2.38(s,6H), 2.06(s,3H).                          44                                                                            4-C.sub.6 H.sub.4 -C.sub.6 H.sub.5                                                 36         7.2-7.8(m,)H), 3.93(s,2H), 3.23(s,3H), 2.60(d,2H), 2.26                            (s,6H), 2.00(s,3H).                                      45                                                                            4-CH.sub.3 OC.sub.6 H.sub.4 *                                                      37                                                                       46                                                                            3-Cl-4-HOC.sub.6 H.sub.3                                                           36         6.78-7.33(m,3H), 3.78(s,2H), 3.25(s,3H), 2.63(bs,2H),                         2.28                                                                               (s,6H), 2.03(s,3H).                                      47                                                                            3,4-(Cl).sub.2 C.sub.6 H.sub.3                                                     37         7.2-7.6(m,3H), 3.93(s,2H), 3.33(s,3H), 2.66(d,2H), 2.31                            (s,6H), 2.08(s,3H).                                      48   2-thienyl  36   6.8-7.4(m,3H), 5.06(s,2H), 3.33(s,3H), 2.72(s,2H),                            2.33                                                                          (s,6H), 2.10(s,3H).                                      49   5-methyl-2-thienyl                                                                       36   6.38-6.72(m,2H), 3.98(s,2H), 3.31 and 3.25 ( ,3H),                            2.61                                                                          (d,2H), 2.43(s,3H), 2.28(s,6H), 2.03(s,3H).              50   5-bromo-2-thienyl                                                                        36   6.65-7.00(m,2H), 4.08(s,2H), 3.40 and 3.35 ( ,3H),                            2.66                                                                          (bs,2H), 2.33(s,6H), 2.08(s,3H).                         51   2-furyl    36   7.3(m,1H), 6.16(m,2H), 3.87(s,2H), 3.12(s,3H),                                2.67(bs,2H),                                                                  2.28(s,6H), 2.03(s,3H).                                  52   5-methyl-2-furyl                                                                         36   5.93(d,2H), 3.83(s,2H), 3.23(s,3H), 2.66(bs,2H),                              2.30(s,9H),                                                                   2.06(s,3H).                                              53   5-hydroxymethyl-2-                                                                       36   6.15(b,2H), 4.55(s,2H), 3.86(s,2H), 3.23(s,3H),                               2.66(bs,2H),                                                  furyl           2.30(s,6H), 2.05(s,3H).                                  54   2-tetrahydrofuryl                                                                        37   3.35(s,3H), 2.63(bs,2H), 2.30(s,6H), 2.01(s,3H).         55   2-tetrahydropyranyl                                                                      37   3.43(s,3H), 2.68(bs,2H), 2.35(s,6H), 2.10(s,3H).         56   2-Δ.sup.5 -dihydropyranyl                                                          37   6.33(bd,1H), 3.35(s,3H), 2.61(bs,2H), 2.28(s,6H),                             2.05(s,                                                                       3H).                                                     57   2-pyridyl  37   8.56(bd,1H), 7.1-7.8(m,3H), 4.13(s,2H), 3.35(s,3H),                           2.70                                                                          (d,2H), 2.33(s,6H), 2.06(s,3H).                          58   2-pyridyl* 37                                                            59   3-pyridyl  37   4.01(s,2H), 3.35(s,3H), 2.66(bs,2H), 2.31(s,6H),                              2.08(s,3H).                                              60   4-pyridyl  37   8.60(d,2H), 7.36(bd,2H), 4.00(s,2H), 3.33(s,3H),                              2.66(bs,                                                                      2H), 2.28(s,6H), 2.06(s,3H).                             61   6-methyl-2-pyridyl                                                                       37   6.8-7.6(m,3H), 4.00(s,2H), 3.35(s,3H), 2.63(bs,2H),                           2.35                                                                          (s,3H), 2.28(s,6H), 2.05(s,3H).                          62   5-methyl-2-pyridyl                                                                       36   8.38(bs,1H), 7.0-7.6(m,2H), 4.03(s,2H), 3.30(s,3H),                           2.67                                                                          (bs,2H), 2.33(s,9H), 2.06(s,3H).                         63   3-methyl-2-pyridyl                                                                       36   8.33(bs,1H), 6.83-7.5(m,2H), 4.00(s,2H), 3.23(s,3H),                          2.66                                                                          bs,2H), 2.33(s,3H), 2.30(s,6H), 2.03(s,3H).              64   3-hydroxy-2-pyridyl                                                                      36   7.0-8.0(m,3H), 3.40(s,3H), 2.68(d,2H), 2.31(s,6H),                            2.08                                                                          (s,3H).                                                  65   2-pyrrolyl 36   6.78(m,1H), 5.92-6.25(m,2H), 4.01(s,2H), 3.35(s,3H),                          2.70                                                                          (bs,2H), 2.33(s,6H), 2.08(s,3H).                         66   1-methyl-2-pyrrolyl                                                                      36   6.62(m,1H), 6.05(m,2H), 3.92(s,2H), 3.75(s,3H),                               3.26(s,3H),                                                                   2.68(bs,2H), 2.31(s,6H), 2.06(s,3H).                     67   5-chloro-2-pyridyl                                                                            8.46(m,1H), 7.50-7.66(m,2H), 4.08(s,2H), 3.33(s,3H),                          2.66                                                                          (d,2H), 2.30(s,6H), 2.06(s,3H).                          68   2-pyridyl  37   8.4-8.6(m,1H), 6.9-7.8(m,3H), 3.30(s,3H),                                     2.66(d,2H), 2.30                                                              (s,6H), 2.06(s,3H).                                      69   1-morpholino                                                                             37   3.36(s,3H), 2.30(s,6H), 2.06(s,3H).                       70.sup.+                                                                          C.sub.6 H.sub.5                                                                          37   7.0(s,5H), 3.39(s,2H), 3.30(s,3H), 2.83(d,2H),                                2.33(s,6H).                                               71.sup.+                                                                     4-ClC.sub.6 H.sub.4                                                                37         7.33(s,4H), 3.90(s,2H), 3.33(s,3H), 2.83(d,2H),                               2.33(s,6H).                                                    72.sup.+                                                                     3-ClC.sub.6 H.sub.4                                                                37         7.2-7.6(m,4H), 3.93(s,2H), 3.30(s,3H), 2.83(d,2H), 2.33                            (s,6H).                                                  __________________________________________________________________________     *= single epimer (separated chromatographically on silica gel according t     Example 36)?                                                                  .sup.+ = R.sub.1 = H                                                     

EXAMPLE 73

Utilizing the procedures of Examples 36 and 37, the compounds listedbelow are prepared from appropriate reactants. When using an11,2'-dialkanoyl-4"-deoxy-4"-oxo(or 4"-amino)-oleandomycin as reactant,isopropanol is used as solvent to avoid hydrolysis of the 2'-alkanoylgroup.

    ______________________________________                                         ##STR10##                                                                

    ______________________________________                                        R.sub. 1                                                                              R.sub.2 Z.sub.1          Method                                       ______________________________________                                        Pr      H       C.sub.6 H.sub.5  36                                           Pr      H                                                                     4-ClC.sub.6 H.sub.4                                                                   36                                                                    Pr      H                                                                     4-HOC.sub.6 H.sub.4                                                                   37                                                                    Pr      H                                                                     3-CH.sub.3 OC.sub.6 H.sub.4                                                           37                                                                    Pr      H                                                                     2-CH.sub.3 C.sub.6 H.sub.4                                                            37                                                                    Pr      H                                                                     4-C.sub.6 H.sub.4 C.sub.6 H.sub.5                                                     36                                                                    Pr      H                                                                     4-CH.sub.3 OC.sub.6 H.sub.4                                                           37                                                                    Pr      H                                                                     2-HOCH.sub.2 C.sub.6 H.sub.4                                                          37                                                                    Pr      H                                                                     3-HOCH.sub.2 C.sub.6 H.sub.4                                                          37                                                                    Pr      H                                                                     3-BrC.sub.6 H.sub.4                                                                   37                                                                    Pr      H                                                                     4-FC.sub.6 H.sub.4                                                                    37                                                                    Pr      H                                                                     4-HSC.sub.6 H.sub.4                                                                   37                                                                    Pr      H                                                                     3-CF.sub.3 C.sub.6 H.sub.4                                                            37                                                                    Pr      H                                                                     4-(CH.sub.3).sub.2 NC.sub.6 H.sub.4                                                   37                                                                    Pr      H                                                                     3-CNC.sub.6 H.sub.4                                                                   37                                                                    Pr      H                                                                     4-n-C.sub.3 H.sub.7 C.sub.6 H.sub.4                                                   36                                                                    Pr      H                                                                     4-n-C.sub.4 H.sub.9 OC.sub.6 H.sub.4                                                  36                                                                    Pr      H                                                                     3-C.sub.2 H.sub.5 C.sub.6 H.sub.4                                                     36                                                                    Pr      H                                                                     4-CH.sub.3 SC.sub.6 H.sub.4                                                           36                                                                    Pr      H                                                                     4-C.sub.3 H.sub.7 SO.sub.2 C.sub.6 H.sub.4                                            36                                                                    Ac      H                                                                     4-HOCH.sub.2 C.sub.6 H.sub.4                                                          37                                                                    Ac      H                                                                     4-CF.sub.3 C.sub. 6 H.sub.4                                                           37                                                                    Ac      H                                                                     2-FC.sub.6 H.sub.4                                                                    36                                                                    Ac      H                                                                     4-BrC.sub.6 H.sub.4                                                                   36                                                                    Ac      H                                                                     3-(CH.sub.3).sub.2 NC.sub.6 H.sub.4                                                   37                                                                    Ac      H                                                                     4-CNC.sub.6 H.sub.4                                                                   37                                                                    Ac      H                                                                     4-t-C.sub.4 H.sub.9 C.sub.6 H.sub.4                                                   37                                                                    Ac      H                                                                     4-n-C.sub.3 H.sub.7 OC.sub.6 H.sub.4                                                  36                                                                    Ac      H                                                                     4-n-C.sub.4 H.sub.9 C.sub.6 H.sub.4                                                   37                                                                    Ac      H                                                                     3-i-C.sub.3 H.sub.7 SC.sub.6 H.sub.4                                                  36                                                                    Ac      H                                                                     4-HO.sub.3 SC.sub.6 H.sub.4                                                           36                                                                    Ac      H                                                                     3-HO.sub.3 SC.sub.6 H.sub.4                                                           36                                                                    Ac      H                                                                     3-H.sub.2 NCOC.sub.6 H.sub.4                                                          36                                                                    Ac      H                                                                     4-H.sub.2 NSO.sub.2 C.sub.6 H.sub.4                                                   36                                                                    Ac      H                                                                     2-H.sub.3 COCOC.sub.6 H.sub.4                                                         36                                                                    Ac      H                                                                     4-H.sub.4 C.sub.9 OCOC.sub.6 H.sub.4                                                  36                                                                    Pr      H                                                                     4-H.sub.5 C.sub.2 OCOC.sub.6 H.sub.4                                                  36                                                                    Pr      H                                                                     2-HO.sub.3 SC.sub.6 H.sub.4                                                           36                                                                    Pr      H                                                                     3-H.sub.2 NCOC.sub.6 H.sub.4                                                          36                                                                    Ac      Ac      C.sub.6 H.sub.5  37                                           Ac      Ac                                                                    4-ClC.sub.6 H.sub.4                                                                   37                                                                    Ac      Ac                                                                    4-CH.sub.3 OC.sub.6 H.sub.4                                                           37                                                                    Ac      Ac                                                                    4-HOCH.sub.2 C.sub.6 H.sub.4                                                          36                                                                    Ac      Ac                                                                    2-HO.sub.3 SC.sub.6 H.sub.4                                                           36                                                                    Ac      Ac                                                                    2-CH.sub.3 SO.sub.2 C.sub.6 H.sub.4                                                   36                                                                    Pr      Pr       C.sub.6 H.sub.5 36                                           Pr      Pr                                                                    3-C.sub.6 H.sub.4 C.sub.6 H.sub.5                                                     36                                                                    Pr      Pr                                                                    4-H.sub.2 NSO.sub.2 C.sub.6 H.sub.4                                                   36                                                                    Pr      Pr                                                                    2-CF.sub.3 C.sub.6 H.sub.4                                                            36                                                                    Ac      H                                                                     3,5-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                  37                                                                    Ac      H                                                                     2,6-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                37                                                                    Ac      H                                                                     3,5-(F).sub.2 C.sub.6 H.sub.3                                                         36                                                                    Ac      H                                                                     2,4-(Br).sub.2 C.sub.6 H.sub.3                                                        36                                                                    Ac      H                                                                     3,4-(HO).sub.2 C.sub.6 H.sub.3                                                        36                                                                    Pr      H                                                                     2,4-(HO).sub.2 C.sub.6 H.sub.3                                                        36                                                                    Pr      H                                                                     2-Br-5-HOC.sub.6 H.sub.3                                                              36                                                                    Pr      H                                                                     4-Cl-3-FC.sub.6 H.sub.3                                                               36                                                                    Pr      H                                                                     2,3-(OCH.sub.2 O)C.sub.6 H.sub.3                                                       36*                                                                  Ac      H                                                                     3,4-(OCH.sub.2 CH.sub.2 O)C.sub.6 H.sub.3                                              36*                                                                  Ac      H                                                                     3-CH.sub.3 -6-ClC.sub.6 H.sub.3                                                        36*                                                                  H       H       C.sub.6 H.sub.5  37                                           H       H                                                                     2-ClC.sub.6 H.sub.4                                                                   37                                                                    H       H                                                                     2,6-(Cl).sub.2 C.sub.6 H.sub.3                                                        36                                                                    H       H                                                                     2,4-(HO).sub.2 C.sub.6 H.sub.3                                                        36                                                                    H       H                                                                     3-Cl-4-HOC.sub.6 H.sub.3                                                              36                                                                    H       H                                                                     2-HO.sub.3 SC.sub.6 H.sub.4                                                           36                                                                    H       H                                                                     4-C.sub.2 H.sub.5 C.sub.6 H.sub.4                                                     36                                                                    H       H                                                                     3-CH.sub.3 OC.sub.6 H.sub.4                                                           37                                                                    H       H                                                                     2,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                37                                                                    H       H                                                                     2-HOCH.sub.2 C.sub.6 H.sub.4                                                          36                                                                    H       H                                                                     3-(CH.sub.3).sub.2 NC.sub.6 H.sub.4                                                   36                                                                    H       H                                                                     4-H.sub.2 NSO.sub.2 C.sub.6 H.sub.4                                                   36                                                                    H       H                                                                     2-Cl-6-FC.sub.6 H.sub.3                                                               36                                                                    H       H                                                                     4-HO-3-CH.sub.3 OC.sub.6 H.sub.3                                                      36                                                                    H       H                                                                     2,3-(OCH.sub.2 O)C.sub.6 H.sub.3                                                       36*                                                                  H       H                                                                     3-BrC.sub.6 H.sub.4                                                                   36                                                                    H       H                                                                     2-C.sub.2 H.sub.5 C.sub.6 H.sub.4                                                     37                                                                    Ac      H                                                                     4-i-C.sub.4 H.sub.9 OC.sub.6 H.sub.4                                                  37                                                                    Ac      H                                                                     2-CH.sub.3 SO.sub.2 C.sub.6 H.sub.4                                                   36                                                                    H       H                                                                     4-C.sub.4 H.sub.9 C.sub.6 H.sub.4                                                     37                                                                    H       H                                                                     4-CF.sub.3 C.sub.6 H.sub.4                                                            36                                                                    H       H                                                                     2-C.sub.2 H.sub.5 OCOC.sub.6 H.sub.4                                                  36                                                                    H       H                                                                     3-H.sub.2 NCOC.sub.6 H.sub.4                                                          36                                                                    H       H                                                                     3-CNC.sub.6 H.sub.4                                                                   36                                                                    H       H                                                                     2-HSC.sub.6 H.sub.4                                                                   36                                                                    Ac      H                                                                     3-CH.sub.3 -6-SHC.sub.6 H.sub.3                                                       36                                                                    H       H                                                                     2-CH.sub.3 -5-FC.sub.6 H.sub.3                                                        36                                                                    H       H                                                                     3-CH.sub.3 -6-CH.sub.3 SC.sub.6 H.sub.3                                               36                                                                    H       H                                                                     2-Br-4-CH.sub.3 C.sub.6 H.sub.3                                                       36                                                                    Pr      H                                                                     2-C.sub.4 H.sub.9 O-5-ClC.sub.6 H.sub.3                                               36                                                                    Ac      Ac                                                                    2-CH.sub.3 -4-HOC.sub.6 H.sub.3                                                       36                                                                    Ac      Ac                                                                    3-C.sub.2 H.sub.5 O-4-HOC.sub.6 H.sub.3                                               36                                                                    Ac      Ac                                                                    4-n-C.sub.3 H.sub.7 SO.sub.2 C.sub.6 H.sub.4                                          36                                                                    Pr      Pr                                                                    2,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                37                                                                    Pr      H                                                                     4-HSC.sub.6 H.sub.4                                                                   36                                                                    Ac      Ac                                                                    2-Cl-3-HOC.sub.6 H.sub.3                                                              37                                                                    Ac      H                                                                     3-thienyl                                                                             36                                                                    Ac      H                                                                     5-Cl-2-thienyl                                                                        36                                                                    Ac      H                                                                     3-Br-2-thienyl                                                                        36                                                                    Ac      H                                                                     3-HO-2-thienyl                                                                        36                                                                    Ac      H                                                                     5-Br-3-thienyl                                                                        36                                                                    Ac      H                                                                     5-Cl-2-furyl                                                                          36                                                                    Ac      H                                                                     2-Cl-3-furyl                                                                          36                                                                    Ac      H                                                                     4-HOCH.sub.2 -3-furyl                                                                 36                                                                    Ac      H                                                                     6-Br-2-pyridyl                                                                        36                                                                    Ac      H                                                                     3-HO-4-pyridyl                                                                        36                                                                    Ac      Ac                                                                    3-thienyl                                                                             36                                                                    Ac      Ac                                                                    2-CH.sub.3 -4-pyridyl                                                                 36                                                                    Ac      Ac                                                                    4-Br-2-pyrrolyl                                                                       36                                                                    Pr      H                                                                     3-pyrrolyl                                                                            36                                                                    Pr      H                                                                     1-CH.sub.3 -2-pyrrolyl                                                                36                                                                    Pr      H                                                                     6-HOCH.sub.2 -2-pyridyl                                                               36                                                                    Pr      Pr                                                                    2-pyridyl                                                                             36                                                                    Pr      Pr                                                                    3-HO-2-pyridyl                                                                        36                                                                    Pr      Pr                                                                    2-dihydropyranyl                                                                      36                                                                    H       H                                                                     2-pyridyl                                                                             36                                                                    H       H                                                                     2-thienyl                                                                             36                                                                    H       H                                                                     4-Br-2-pyrrolyl                                                                       36                                                                    ______________________________________                                    

EXAMPLE 74 Acid Addition Salts

To a solution of 11-acetyl-4"-deoxy-4"-(2-fluoroanilino)-oleandomycin(1.0 mmole) in methanol (50 ml.) is added an equimolar proportion ofhydrogen chloride and the reaction mixture stirred at room temperaturefor one hour. Removal of the solvent by evaporation affords thehydrochloride salt.

In like manner, the above-named compound and the compounds of Examples1-73 are converted to their hydrochloride, hydrobromide, sulfate,acetate, butyrate, citrate, glycolate, tartrate, stearate, pamoate,fumarate, benzoate and aspartate salts.

When the reactant is an11,2'-dialkanoyl-4"-deoxy-4"-anilino-oleandomycin, isopropanol is usedas solvent.

PREPARATION A 11,2'-Diacetyl-4"-deoxy-4"-oxo-oleandomycin

To 4.5 g. of N-chlorosuccinimide, 50 ml. of benzene and 150 ml. oftoluene in a dry flask fitted with a magnetic stirrer and nitrogen inletand cooled to -5° C. is added 3.36 ml. of dimethylsulfide. Afterstirring at 0° C. for 20 minutes, the contents are cooled to -25° C. andtreated with 5.0 g. of 11,2'-diacetyl-oleandomycin in 100 ml. oftoluene. Cooling and stirring are continued for 2 hours followed by theaddition of 4.73 ml. of triethylamine. The reaction mixture is allowedto stir at 0° C. for 15 minutes, and is subsequently poured into 500 ml.of water. The pH is adjusted to 9.5 with 1N aqueous sodium hydroxide andthe organic layer separated, washed with water and a brine solution anddried over sodium sulfate. Removal of the solvent in vacuo gives 4.9 g.of the desired product as a foam.

NMR (60 MHz) δ_(CDCl).sbsb.3^(TMS) (ppm): 3.48 (s, 3H), 2.61 (m, 2H),2.23 (s, 2H), and 2.03 (s, 6H).

In like manner, the following11,2'-dialkanoyl-4"-deoxy-4"-oxooleandomycins are prepared from thecorresponding 11,2'-dialkanoyl-oleandomycins:

11,2'-dipropionyl-

11-acetyl-2'-propionyl

11-propionyl-2'-propionyl-

PREPARATION B 11-Acetyl-4"-deoxy-4"-oxo-oleandomycin

A solution of 4.0 g. of 11,2'-diacetyl-4"-deoxy-4"-oxo-oleandomycin in75 ml. of methanol is allowed to stir at room temperature overnight. Thereaction mixture is concentrated under reduced pressure to give theproduct as a foam. A diethyl ether solution of the residue, on treatmentwith hexane, gives 2.6 g. of the product as a white solid, m.p.112°-117° C.

NMR (60 MHz) δ_(CDCl).sbsb.3^(TMS) (ppm): 3.43 (s, 3H), 2.60 (m, 2H),2.23 (s, 6H), and 2.01 (s, 3H).

Following the above procedures, 11-propionyl-4"-deoxy-4"-oxooleandomycin is prepared from11,2'-dipropionyl-4"-deoxy-4"-oxo-oleandomycin.

PREPARATION C 2'-Acetyl-4"-deoxy-4"-oxo-oleandomycin

Dimethylsulfide (0.337 ml.) is added to a turbid solution of 467 mg. ofN-chlorosuccinimide in 20 ml. of toluene and 6 ml. of benzene cooled to-5° C. and maintained under a nitrogen atmosphere. After stirring at 0°C. for 20 minutes the mixture is cooled to -25° C. and 1.46 g. of2'-acetyloleandomycin and 15 ml. of toluene are added. Stirring iscontinued for 2 hours at -20° C. followed by the addition of 0.46 ml. oftriethyl amine. The reaction mixture is maintained at -20° C. for anadditional 5 minutes and then allowed to warm to 0° C. The mixture ispoured, with stirring, into 50 ml. of water and 50 ml. of ethyl acetate.The pH of the aqueous mixture is adjusted to 9.5 by addition of aqueoussodium hydroxide solution. The organic layer is subsequently separated,dried over sodium sulfate and concentrated in vacuo to a white foam (1.5g.). Trituration with diethyl ether gives 864 mg. of crude product,which on recrystallization twice from methylene chloride-diethyl ethergives 212 mg. of the pure product, m.p. 183°-185.5° C.

Anal. Calc'd for C₃₇ H₆₁ O₁₃ N: C, 61.1; H, 8.5; N, 1.9. Found: C, 60.9;H, 8.4; N, 1.9.

NMR (60 MHz) δ_(CDCl).sbsb.3^(TMS) (ppm): 5.60 (m, 1H), 3.50 (s, 3H),2.73 (m, 2H), 2.23 (s, 6H) and 2.03 (s, 3H).

In like manner, 2'-propionyl-4"-deoxy-4"-oxo-oleandomycin is preparedfrom 2'-propionyloleandomycin.

PREPARATION D 4"-Deoxy-4"-oxo-oleandomycin

A solution of 1.0 g. of 2'-acetyl-4"-deoxy-4"-oxo-oleandomycin in 20 ml.of methanol is allowed to stir at room temperature overnight. Thesolution is concentrated in vacuo to give the desired product as a whitefoam, 937 mg.

NMR (60 MHz) δ_(CDCl).sbsb.3^(TMS) (ppm): 5.60 (m, 1H), 3.50 (s, 3H),2.85 (m, 2H), and 2.26 (s, 6H).

Similarly, 2'-propionyl-4"-deoxy-4"-oxo-oleandomycin is hydrolyzed to4"-deoxy-4"-oxo-oleandomycin.

PREPARATION E 11-Acetyl-4"-deoxy-4"-amino-oleandomycin

To a suspension of 10% palladium-on-charcoal (10 g.) in methanol (100ml.) is added ammonium acetate (21.2 g.) and the resulting slurry istreated with a solution of 11-acetyl-4"-deoxy-4"-oxo-oleandomycin (20g.) in 100 ml. of the same solvent. The suspension is shaken at roomtemperature in a hydrogen atmosphere at an initial pressure of 50 p.s.i.After 1.5 hours, the catalyst is filtered and the filtrate is added withstirring to a mixture of water (1200 ml.) and chloroform (500 ml.). ThepH is adjusted from 6.4 to 4.5 and the organic layer is separated. Theaqueous layer, after a further extraction with chloroform (500 ml.), istreated with ethyl acetate (500 ml.) and the pH adjusted to 9.5 with 1Nsodium hydroxide. The ethyl acetate layer is separated and the aqueouslayer extracted again with ethyl acetate. The ethyl acetate extracts arecombined, dried over sodium sulfate and concentrated to a yellow foam(18.6 g.), which on crystallization from diisopropyl ether, provides6.85 g. of the purified product, m.p. 157.5°-160° C.

NMR (δ, CDCl₃): 3.41 (3H)s, 2.70 (2H)m, 2.36 (6H)s and 2.10 (3H)s.

The other epimer, which exists in the crude foam to the extent of20-25%, is obtained by gradual concentration and filtration of themother liquors.

In like manner, the following mono-alkanoyl and dialkanoyl esters of4"-deoxy-4"-amino-oleandomycin are prepared from the appropriatemono-alkanoyl and dialkanoyl 4"-deoxy-4"-oxo-oleandomycins. When a2'-ester is prepared, isopropanol is used as solvent.

11,2'-diacetyl-

2'-acetyl-

2'-propionyl-

4 11,2'-dipropionyl -dipropronyl-

11-propionyl-

11-acetyl-2'-propionyl-

11-propionyl-2'-acetyl-

PREPARATION F 4"-Deoxy-4"-amino-oleandomycin

A solution of 2'-acetyl- 4"-deoxy-4"-oxo-oleandomycin (20 g.) inmethanol (125 ml.), after stirring at room temperature overnight, istreated with ammonium acetate (21.2 g.). The resulting solution iscooled in an ice bath and treated with sodium cyanoborohydride (1.26g.). The cooling bath is then removed and the reaction mixture allowedto stir at room temperature for 2 hours. The reaction is poured intowater (600 ml.) and diethyl ether (600 ml.) and the pH adjusted from 8.3to 7.5. The ether layer is separated and the aqueous phase extractedwith ethyl acetate. The extracts are set aside and the pH of the aqueousadjusted to 8.25. The diethyl ether and ethyl acetate extracts made atthis pH are also set aside, and the pH raised to 9.9. The diethyl etherand ethyl acetate extracts at this pH are combined, washed successivelywith water (1x) and a saturated brine solution and dried over sodiumsulfate. The latter extracts, taken at pH 9.9, are concentrated to afoam and chromatographed on silica gel (160 g.), using chloroform as theloading solvent and initial eluate. After eleven fractions, 12 ml. perfraction are taken, the eluate is changed to 5% methanol-95% chloroform.At fraction 370 the eluate is changed to 10% methanol-90% chloroform andat fraction 440, 15% methaol-85% chloroform is used. Fractions 85-260are combined and concentrated in vacuo to dryness to provide 2.44 g. ofthe desired product.

NMR (δ, CDCl₃): 5.56 (1H)m, 3.36 (3H)s, 2.9 (2H)m and 2.26 (6H)s.

What is claimed is:
 1. An epimeric compound having the formula ##STR11##and the pharmaceutically acceptable salts thereof wherein each of R₁ andR₂ is selected from the group consisting of hydrogen, alkanoyl havingfrom two to three carbon atoms and is selected from the group consistingof acetyl and propionyl;Z is selected from the group consisting of afirst subgroup consisting of ##STR12## a second subgroup consisting of##STR13## and a third subgroup consisting of

    --CH.sub.2 -heterocyclyl;

wherein X is selected from the group consisting of hydrogen, chloro,bromo, fluoro, alkyl having from one to four carbon atoms, alkoxy havingfrom one to four carbon atoms, hydroxy, mercapto, trifluoromethyl,N(CH₃)₂, cyano, thioalkyl having from one to four carbon atoms,sulfonylalkyl having from one to four carbon atoms, sulfamyl, sulfo,carbamyl, hydroxymethyl and carbalkoxy having from one to four carbonatoms in the alkoxy group; X₁ is selected from the group consisting ofchloro, bromo, fluoro, methyl, methoxy, hydroxy, mercapto andtrifluoromethyl; Y is selected from the group consisting of choro,bromo, fluoro, methyl, methoxy and hydroxy; and X₁ and Y when takentogether are located on adjacent carbon atoms and are alkylenedioxy andare selected from the group consisting of methylenedioxy andethylenedioxy; and heterocyclyl is selected from the group consisting of(a) thienyl, furyl, pyridyl and pyrrolyl and substituted derivativesthereof wherein the substituent is selected from the group consisting ofmethyl, chloro, bromo, hydroxy and hydroxymethyl; and (b)2-tetrahydrofuryl, 2-dihydropyranyl, 2-tetrahydropyranyl and morpholino.2. A compound according to claim 1 wherein Z is ##STR14## R₂ is hydrogenand R₁ is alkanoyl.
 3. A compound according to claim 2 wherein X isfluoro.
 4. A compound according to claim 2 wherein X is alkoxy.
 5. Acompound according to claim 2 wherein X is alkyl.
 6. A compoundaccording to claim 2 wherein X is carbalkoxy.
 7. A compound according toclaim 3 wherein X is 2-fluoro and R₁ is acetyl.
 8. A compound accordingto claim 4 wherein X is 4-methoxy and R₁ is acetyl.
 9. A compoundaccording to claim 6 wherein X is 2-carbomethoxy and R₁ is acetyl.
 10. Acompound according to claim 1 wherein Z is ##STR15## R₂ is hydrogen andR₁ is alkanoyl.
 11. A compound according to claim 10 wherein X₁ is3-chloro and Y is 4-chloro.
 12. A compound according to claim 10 whereinX₁ is 2-methoxy and Y is 4-methoxy.
 13. A compound according to claim 1wherein Z is ##STR16## R₂ is hydrogen and R₁ is alkanoyl.
 14. A compoundaccording to claim 13 wherein x is chloro.
 15. A compound according toclaim 1 wherein Z is ##STR17## R₂ is hydrogen and R₁ is alkanoyl.
 16. Acompound according to claim 15 wherein X₁ is 3-chloro, Y is 4-chloro andR₁ is acetyl.
 17. A compound according to claim 13 wherein X₁ is4-hydroxy; Y is 3-chloro and R₁ is acetyl.
 18. A compound according toclaim 1 wherein Z is --CH₂ -heterocyclyl wherein heterocyclyl ispyridyl; R₂ is hydrogen and R₁ is alkanoyl.
 19. A compound according toclaim 1 wherein Z is --CH₂ -heterocyclyl wherein heterocyclyl is2-dihydropyranyl; R₁ is acetyl and R₂ is hydrogen.
 20. A compoundaccording to claim 1 wherein Z is --CH₂ -heterocyclyl whereinheterocyclyl is pyrrolyl; R₁ is alkanoyl and R₂ is hydrogen.